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Show Should Patients With Bartonella Neuroretinitis Receive Treatment? M. Tariq Bhatti, MD, Michael S. Lee, MD Neuroretinitis refers to focal inflammation of the optic nerve and retina and is typically characterized clinically by painless loss of vision, optic disc swelling, and macular exudates, usually in a star-like pattern. Although a wide variety of infectious and noninfectious diseases are associated with neuroretinitis, Bartonella is the most common infectious etiology. However, whether patients with Bartonella neuroretinitis should be treated remains controversial. Two experts debate this topic. Pro: Patients With Bartonella Neuroretinitis Should Receive Treatment: Michael S. Lee, MD Bartonella-related neuroretinitis likely represents an intra-ocular inflammatory or immune response to systemic exposure to Bartonella henselae or Bartonella quintana rather than true intraocular infection. Among immunocompetent individuals, visual loss is typically self-limited, and the visual prognosis is often excellent without treatment (1). There-fore, even though I believe that most patients with self-limited Bartonella neuroretinitis may not require treatment, I think that there is a compelling rationale for offering treatment to certain patients. Among patients with systemic Bartonellosis, studies have shown that antimicrobial therapy shortens the symptomatic illness. In many instances, systemic symptoms of fever and lymphadenopathy can accompany Bartonella neuroretinitis, and this may indicate need for therapy (1). B. henselae has shown susceptibility in vitro to rifampin, ciprofloxacin, gentamicin, azithromycin, clarithromycin, and trimetho-prim- sulfamethoxazole (2). Bass et al (3) randomized patients with B. henselae lymphadenitis to receive either azithromycin or placebo. At 1 month follow-up, 50% of the azithromycin group achieved reduction of 80% of lymph node volume compared with only 7% in the placebo group. Although I am unaware of any randomized con-trolled clinical trials for the treatment of Bartonella neuro-retinitis, in a retrospective review, Reed et al (4) demonstrated quicker visual recovery and shortened disease course with antibiotic use compared with historical controls. A combination of doxycycline and rifampin (4) or cipro-floxacin (5) has been reportedly beneficial for immunocom-petent patients with Bartonella neuroretinitis. However, immunocompromised patients with Bartonella neuroretini-tis tend to experience worse visual outcomes. This includes individuals with acquired immunodeficiency syndrome, transplant patients and those with HIV/AIDS. In this patient group, erythromycin or doxycycline can significantly mitigate visual loss (6). Although doxycycline is more effec-tive against Bartonella, erythromycin is preferred for chil-dren under 8 years because of tooth discoloration with doxycycline use. Neuroretinitis represents a descriptive term for optic disc edema with a macular star, and, although B. henselae and Quintana are the most common source, one cannot assume that all cases result from these organisms (7). Toxoplasmosis (8), syphilis (9), Lyme (10), tuberculosis (11), sarcoidosis (12), inflammatory bowel disease (13), polyarteritis nodosa (14), and Rocky Mountain spotted fever (15) among others have been associated with neuroretinitis. At the time of neuroretinitis diagnosis, the underlying cause is not always readily apparent. The physician should inquire about pos-sible risk factors such as cat exposure, potential exposure to ticks or tuberculosis, or sexual contact. Other clues include a positive review of systems for fever, myalgias, headache, productive cough, or skin rash. In the majority of cases, the exact cause of neuroretinitis is not established by the time the patient leaves the office. Therefore, one might consider treating with antibiotics until the laboratory workup is complete. Many results in the differential diagnosis can return within a day; however, Quantiferon gold can take 2-4 days, and the laboratory results for B. henselae, B. quintana, toxoplasmosis, and Rocky Mountain spotted fever often take several days or more to return depending on the proximity of the testing Departments of Ophthalmology and Neurology (MTB), Duke Uni-versity Eye Center, Durham, North Carolina; and Departments of Ophthalmology and Visual Neurosciences, Neurology, and Neuro-surgery (MSL), University of Minnesota, Minneapolis. An unrestricted grant to the Duke Eye Center Department of Oph-thalmology from Research to Prevent Blindness, Inc (New York, NY). The authors report no conflicts of interest. Address correspondence to Michael S. Lee, MD, 420 Delaware Street SE, MMC 493, Minneapolis, MN 55455; E-mail: mikelee@umn.edu 412 Bhatti and Lee: J Neuro-Ophthalmol 2014; 34: 412-416 Point Counter-Point Section Editors: Andrew G. Lee, MD Gregory Van Stavern, MD Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. laboratory. In some cases, acute Bartonella infection shows normal IgM titers. After 4-6 weeks, IgG convalescence titers may rise 4-fold, but this may delay a definitive diag-nosis of Bartonella neuroretinitis. Therefore, I believe that it is reasonable to begin presumptive treatment for neuroretinitis in the following situations: severe visual loss; bilateral involvement; presence of systemic symptoms; immunocompromised state; pro-gressive, protracted clinical course. Bilateral, simultaneous Bartonella neuroretinitis can occur, but more likely repre-sents another infectious or inflammatory etiology (after ruling out malignant hypertension and intracranial hyper-tension). The final diagnosis of Bartonella neuroretinitis is often made after the acute phase of the disease because of the delay in titer availability. To prevent a delay in treatment for other causes of neuroretinitis, while laboratory testing is in progress, the clinician should consider treat-ment with azithromycin, which can treat to a reasonable extent toxoplasmosis (16), Lyme (17), and Bartonella (3). I believe that immunocompromised patients with neuroreti-nitis should receive doxycycline or erythromycin, before the laboratory testing returns (5). In the absence of tuberculosis exposure, I would hold treatment for this before laboratory confirmation. Finally, patients with progressive, protracted, or recurrent neuroretinitis should receive an autoimmune evaluation, and the practitioner may want to initiate sys-temic corticosteroids as an adjunct to azithromycin. Con: Patients With Bartonella Neuroretinitis Should Not Receive Treatment: M. Tariq Bhatti, MD "As to diseases, make a habit of 2 things-to help or at least to do no harm" Hippocrates, Epidemics, Bk. I, Sect. XI. Any intervention, whether it is the institution of a medication, insertion of a medical device or performing an invasive surgical procedure should always be preceded by a risk-benefit analysis. This holds true for a case of Bartonella neuroretinitis as well. Several important questions that should be addressed in the efficacy and safety of Bartonella neuro-retinitis treatment are: 1. Is B. henselae the cause of neuroretinitis? If so what is the science of disease? 2. What is the natural history of Bartonella neuroretinitis? 3. What is the evidence to support treatment and how strong is that evidence? 4. What are the risks of treatment? The following discussion will focus on B. henselae infec-tion in an immunocompetent patient. Immunocompromised patients infected with B. henselae present with clinical man-ifestations and demonstrate disease behavior that is signifi-cantly different from patients with a healthy functioning immune system (18). Is B. henselae the Cause of Neuroretinitis? If So, What Is the Science of Disease? There is little doubt that B. henselae, an aerobic, oxidase-negative, Gram-negative bacillus, is an arthropod/zoonotic transmitted infectious agent that can result in cat scratch disease (CSD); a self-limited systemic illness associated with fever and lymphadenopathy (19). Aside from the ocular complications of neuroretinitis, chorioretinitis, uveitis, and retinal vasculitis (20- 22), B. henselae has also been reported to cause visceral organ (liver and spleen), cerebral, and cardiac disease (2,23,24). Golnik et al (5) were among the first to recognize B. henselae (at the time known as Rochalimaea henselae) as the causative agent of neuroretinitis. Intravenous fluorescein angiography has shown that the subretinal fluid and macu-lar exudates are the result of leakage from the surface vasculature of the optic disc. Increased knowledge of the pathophysiology of B. hense-lae has provided insight into the clinical manifestations and complications of the infectious process, and a nidus for the improvement in and the development of novel treatment strategies (25,26). It is beyond the scope of this discussion to detail the molecular mechanism by which B. henselae infects humans, but in broad terms, it has a predilection to infect endothelial and erythrocyte cells. Surface specific antigens allow binding to the extracellular matrix and nucle-ated cells. Once inside the cell, the bacterium avoids the defensive strategy of the host cell, specifically the lysosomal degradation pathway, by residing in vacuoles and introduc-ing anti-endocytic proteins into the cytoplasm (27). In addi-tion, B. henselae infection results in angiogenesis through the production of vascular endothelial growth factor and suppression of pericyte cell proliferation (28). What Is the Natural History of Bartonella Neuroretinitis? The natural history of Bartonella neuroretinitis is not known because the published data are composed of case series with relatively small numbers, admixed with treated and untreated patients with neuroretinitis, and various other ocular complications (20-22). Chi et al (29) pub-lished the largest series of patients with cat scratch optic neuropathy (62 eyes of 53 patients) and found that the overall visual outcome was excellent at final follow-up with 68% of patients retaining a vision of 20/40 or better. How-ever, many of the patients in the study were treated, thus not allowing for an analysis of the natural history of the disease. Bhatti and Lee: J Neuro-Ophthalmol 2014; 34: 412-416 413 Point Counter-Point Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. What Is the Evidence to Support Treatment and How Strong Is That Evidence? A variety of antibiotics have been recommended for B. henselae infection including erythromycin, amoxicillin, gentamicin, rifampin, ceftriaxone, ciprofloxacin, azithromy-cin, and trimethoprim-sulfamethoxazole (2,25). Although records of case reports and case series have suggested a treat-ment benefit of antibiotics for patients with CSD, to date, there has only been one randomized controlled trial (RCT) that has evaluated the benefit of antibiotic therapy; and in that study, there was no improved cure rate with treatment (azithromycin) compared with placebo (30). Published treatment recommendations for Bartonella neuroretinitis should be viewed with caution and if possible self-vetted. For example, in the excellent review article by Rolain et al (2), the authors recommend patients with "ret-initis" be treated with doxycycline and rifampin. The qual-ity of evidence and strength of recommendation was given a score of II and A, respectively. Two references were given to support this grade. The first reference is a textbook chap-ter that states "There is no convincing evidence that anti-biotic treatment affects the course of either complicated or uncomplicated CSD in the immunocompetent patient" (31). The second reference is a retrospective case series reporting the visual outcome of 6 patients treated with anti-biotics (4- to 6-week course of oral doxycycline [100 mg twice daily] and rifampin [300 mg 2 to 3 times daily]) and one patient who received the same antibiotic regiment and a 2-week course of oral prednisone. The study did not include any untreated patients; therefore, the authors com-pared the results of their 7 patients with historical data from 2 case reports, a 4-patient case series, and a retrospective study on the therapeutic outcome of 268 patients with CSD some of whom had neuroretinitis, although the exact num-ber of cases were not reported, but "blindness" was noted in 6% of patients (4,32). It seems clear that the treatment data for Bartonella neuroretinitis is very limited and based solely on data obtained from retrospective, observational open-labeled studies (1). As mentioned earlier, in the largest collection of cat scratch optic neuropathy cases published to date, Chi et al (29) did not find an improved visual outcome in treated (antibiotics, corticosteroids, or both) compared with untreated patients. However, an RCT would be needed to determine whether there is (or is not) a beneficial effect of antibiotic treatment for visual function. If one were to design an RCT using the data from the study of Chi et al, based on the calculations of a two group chi-square test with a 0.050 two-sided significance level with a 90% power to detect the difference between a nontreated group proportion of 0.89 and a treated group proportion of 0.65 (odds ratio of 0.230), the sample size in each group (treatment and pla-cebo) would need to be 63 with total sample size of 126. Given the rarity of Bartonella neuroretinitis, such a recruit-ment goal for an RCT would be very difficult to accomplish and would require a multicenter study. What Are the Risks of Treatment? Both antibiotic and corticosteroid treatments are not innocuous and can be associated with complications, some of which can be severe. It has been estimated that approximately 20% of emergency department visits are because of antibiotic-related adverse events (33). The lax use of antimicrobial agents can result in changes in the normal flora of an individual resulting in disease (e.g., Clostridium difficile colitis) and the development of bacterial resistance (34). The multitude of side effects from corticosteroid treat-ment is well known to most physicians (e.g., diabetes mellitus, gastric ulcer disease, osteoporosis, immunosuppression, avas-cular necrosis) resulting in significant morbidity and in some cases death. However, what may not be appreciated is the fact that even young patients receiving short courses of corticoste-roid treatment can develop adverse side effects. For example, in the Optic Neuritis Treatment Trial, which enrolled patients between the ages of 18 and 46 years, of the 151 pa-tients treated with intravenous methylprednisolone, 2 patients experienced significant complications of acute pancreatitis and acute psychosis (35). Rebuttal: Dr. Lee I agree with Dr. Bhatti that the evidence for treating patients with Bartonella neuroretinitis is sparse, but I don't want to exaggerate the harm. The incidence of community-acquired C. difficile infection in Olmsted County, MN was 9.6 per 100,000 person-years from 1991 to 2005 (36). As for corticosteroids, I would propose limiting treatment to a 2- to 3-week course at most. Although side effects can occur at this dose and duration, a retrospective review of 83 patients treated with at least 1 month of relatively high-dose prednisone and at least 4 months' taper showed a 2-year risk of serious complications of 1% (one patient total, but the authors note that the patient did not follow the prescribed prednisone regimen) (37). It is my belief that a short course of oral antibiotics or oral corticosteroids, in the proper con-text, has a reasonable safety profile. Although the article by Chi et al (29) did not find an association between final visual acuity and the use of sys-temic antibiotic or corticosteroid, there was no randomiza-tion. We know that the patients did not have equal visual acuity at baseline. Treated eyes showed worse initial visual acuity than untreated eyes (count fingers vs 20/126 [corti-costeroids] and 20/200 vs 20/80 [antibiotics]). We do not 414 Bhatti and Lee: J Neuro-Ophthalmol 2014; 34: 412-416 Point Counter-Point Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. know if the groups experienced similar duration of symp-toms before initial evaluation. It is unclear which antibiotic was used in each case, and we cannot lump all antibiotics into the same group. I agree with Dr. Bhatti that an RCT is necessary to determine whether a benefit exists for antibiotic treatment or not. Until such a time, we need an outline for treatment. As noted in my initial discussion, although most patients do not require treatment, it is definitely reasonable to consider antibiotics and/or steroids under certain circum-stances as listed earlier. Rebuttal: Dr. Bhatti To borrow the wonderful aphorism by the great Carl Sagan, "the absence of evidence is not the evidence of absence." Although I made the argument in my opening remarks that immunocompetent patients with Bartonella neuroretinitis do not need to be treated, I must declare that the lack of clinical data does not mean that one should not treat such a patient. In fact, evidence-based medicine implies the practice of implementing clinical evidence and clinical experience (38). As expected, Dr. Lee does a marvelous job explaining the reasons for treating a patient with Bartonella neuroretinitis and succinctly reviews the other causes of neuroretinitis and the proper evaluation of a patient with neuroretinitis. However, I respectfully disagree with the statement "there is a compelling rationale for offering treatment for certain patients" for the simple reason that there is a lack of com-pelling evidence in the literature to offer treatment. It was pointed out that antibiotic treatment of CSD shortens the symptomatic illness (at least some aspects of it) and that in vitro studies have shown B. henselae to be susceptible to a variety of antibiotics. On those 2 points I agree, but I am not convinced that antibiotics have a beneficial effect of visual recovery in patients with Bartonella neuroretinitis. The study of Reed et al (4) is invoked to support the concept that antibiotic therapy helps patients to recover vision quicker and shorten the disease course. As I discussed earlier, this study was a retrospective case series of only 7 patients that was compared with a nebulous historical con-trol group. I do not believe one can use this data to state confidently that the majority of patients with Bartonella neu-roretinitis will benefit from antibiotic therapy. Finally, Dr. Lee refers to the study by Bass et al (3), which random-ized a total of 29 patients with CSD to either azithromycin (14 patients) or placebo (15 patients) and found a favorable difference in the rate and degree of total lymph node volume decrease in the azithromycin group compared with the pla-cebo group. The more clinically relevant finding of the study was the lack of difference between the 2 groups in any of the measured clinical outcomes, those being fever, malaise/fatigue, anorexia/weight loss, headache, and rash or other skin lesions. Dr. Lee and I both agree that at a minimum most immunocompetent patients with Bartonella neuroretinitis do not require treatment. Furthermore, I believe prescribing pharmacological (antibiotic or corticosteroid) therapy for any patient with Bartonella neuroretinitis should not be a "knee jerk" response, but rather a decision derived from thoughtful contemplation about one's own (and colleague's) clinical experience, the limited published clinical evidence and the potential harmful side effects of treatment. CONCLUSIONS Management of Bartonella neuroretinitis is complicated by the rarity of the disorder, known mimickers of optic disc edema with a macular star figure including other infectious and inflammatory diseases, severe papilledema, hypertensive retinopathy, and most importantly an unknown natural history. The decision about when and how to treat should be considered a practice option that is based on careful analysis of the available medical evidence and the characteristics of the individual patient. 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